Influenza Nucleoprotein: Promising Target for Antiviral Chemotherapy

Cianci, Christopher; Gerritz, Samuel W.; Deminie, Carol; Krystal, Mark

doi:10.3851/imp2235

Cited by 45 publications

(39 citation statements)

References 147 publications

(266 reference statements)

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“…It would be interesting to examine whether the RNP assembled in the presence of RSV604 is functional and whether RSV604 is incorporated into virions, which we have not determined. RSV604 did not appear to affect N protein distribution and localization in the infected cells, suggesting that its MoA differs from that of the influenza virus nucleoprotein inhibitor nucleozin, which induces nucleoprotein aggregation and alters its intracellular localization (14)(15)(16). A new RSV N inhibitor with improved potency and physical properties would be desirable to reach the full potential for this class of RSV inhibitors.…”

Section: Discussionmentioning

confidence: 99%

“…However, the MoA and mechanism of resistance for the compound were unclear. The MoA of another class of negativestrand RNA virus nucleoprotein inhibitors, aryl piperazine amides, such as nucleozin, is through inducing nucleoprotein aggregation and altering its localization in influenza virus-infected cells (14)(15)(16). The function of nucleoprotein is well conserved among negativestrand RNA viruses.…”

mentioning

confidence: 99%

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Mechanism of Action for Respiratory Syncytial Virus Inhibitor RSV604

Challa

Scott

Yuzhakov

et al. 2015

Antimicrob Agents Chemother

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Respiratory syncytial virus (RSV) is an enveloped, nonsegmented, negative-sense RNA virus in the family Paramyxoviridae. It is the leading cause of acute lower respiratory tract infections (ALRI) in young children and other high-risk populations worldwide (1). RSV infection has accounted for an estimated 34 million cases of ALRI and over 66,000 deaths among children younger than 5 years in developing countries each year (2). The association of RSV infection with morbidity in elderly patient populations with underlying chronic illnesses (e.g., chronic obstructive pulmonary disease, asthma, and immunocompromised patients) has also been increasingly recognized in recent years (3, 4). Despite decades of research and drug development endeavors, no effective RSV treatment or vaccine is available (1). Ribavirin, a panantiviral and the only approved small-molecule therapy against RSV, has an unclear molecular mechanism of action (MoA) and restricted clinical utility due to its toxicity, limited efficacy, and complexity of use (5). Immunoprophylaxis with RSV-neutralizing antibodies is effective only as a preventive measure, but not as a therapeutic treatment (5).In the past 2 decades, RSV inhibitors in clinical development for RSV therapeutic treatment have primarily targeted viral fusion to prevent infection of new cells. Other early clinical candidates included the small interfering RNA (ALN-RSV01) (6, 7), nucleoside inhibitor (ALS-8176) (8), and nucleoprotein (N) inhibitor (RSV604) (9). These inhibitors have yet to show reported therapeutic efficacy in the clinic against natural RSV infections (10). In two recent phase 2a RSV challenge studies with adult volunteers, the fusion inhibitor GS-5806 (Gilead) and the nucleotide inhibitor ALS-8176 (Alios) demonstrated a reduction in disease symptoms and viral load when dosed at a relatively low viral load and before the onset of symptoms (11). In a phase 2a trial in stem cell transplant patients with RSV infection, RSV604 reduced the viral load and symptoms in the subset of patients with RSV604 plasma exposure reaching 1ϫ the 90% effective concentration (EC 90 ), though not in those with less plasma exposure (12).Of the 11 RSV-encoded proteins, N is one of the most conserved structural proteins and is essential for virus encapsidation by coating the entire viral RNA genome to form the ribonucleoprotein (RNP). Although poorly understood, this multifunctional protein was also found to play an important role in viral RNA replication, mRNA transcription, and virus assembly (3). RSV604, discovered through chemical optimization of an RSV high-throughput screen hit, was reported to be an N inhibitor based on the identification of resistance mutations in the N gene in the escape viruses (9, 13). However, the MoA and mechanism of resistance for the compound were unclear. The MoA of another class of negativestrand RNA virus nucleoprotein inhibitors, aryl piperazine amides, such as nucleozin, is through inducing nucleoprotein aggregation and altering its localization in influenza virus...

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Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

Mechanism of Action for Respiratory Syncytial Virus Inhibitor RSV604

Challa

Scott

Yuzhakov

et al. 2015

Antimicrob Agents Chemother

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“…Viral nucleoprotein (NP) plays multiple roles in viral lifecycle, including nuclear import/export of viral ribonucleoprotein (vRNP) and transcription/replication of the viral genome [8,9,10]. Targeting at the unconventional nuclear localization signal (NLS) of NP by mycalamide analogs results in a reduction of viral replication [11].…”

Section: Introductionmentioning

confidence: 99%

NXT1, a Novel Influenza A NP Binding Protein, Promotes the Nuclear Export of NP via a CRM1-Dependent Pathway

Chutiwitoonchai

Aida

2016

Viruses

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Influenza remains a serious worldwide public health problem. After infection, viral genomic RNA is replicated in the nucleus and packed into viral ribonucleoprotein, which will then be exported to the cytoplasm via a cellular chromosome region maintenance 1 (CRM1)-dependent pathway for further assembly and budding. However, the nuclear export mechanism of influenza virus remains controversial. Here, we identify cellular nuclear transport factor 2 (NTF2)-like export protein 1 (NXT1) as a novel binding partner of nucleoprotein (NP) that stimulates NP-mediated nuclear export via the CRM1-dependent pathway. NXT1-knockdown cells exhibit decreased viral replication kinetics and nuclear accumulated viral RNA and NP. By contrast, NXT1 overexpression promotes nuclear export of NP in a CRM1-dependent manner. Pull-down assays suggest the formation of an NXT1, NP, and CRM1 complex, and demonstrate that NXT1 binds to the C-terminal region of NP. These findings reveal a distinct mechanism for nuclear export of the influenza virus and identify the NXT1/NP interaction as a potential target for antiviral drug development.

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“…However, the precise mechanism(s) of action has not been investigated in detail. While the compounds clearly inhibit viral transcription, either from RNPs reconstituted in cells by plasmid transfection or from RNPs purified from virus (15)(16)(17), discrepancies between the 50% inhibitory concentrations for overall virus replication versus transcription raise the possibility of more than one mechanism of action (14).…”

mentioning

confidence: 99%

“…One attractive strategy is to target NP, since this protein plays many essential roles in vRNA synthesis, genome trafficking, and virus assembly (4,12). Recently, several groups identified NP-interacting molecules able to inhibit virus replication (13)(14)(15)(16)(17). These compounds, nucleozin or related derivatives, bind to at least two sites on NP and appear to act as "molecular staples" that promote the formation of higher-order oligomers or aggregates by stabilizing monomer interactions.…”

mentioning

confidence: 99%

Nucleozin Targets Cytoplasmic Trafficking of Viral Ribonucleoprotein-Rab11 Complexes in Influenza A Virus Infection

Amorim

Kao

Digard

2013

J Virol

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dNovel antivirals are needed to supplement existing control strategies for influenza A virus (IAV). A promising new class of drug, exemplified by the compound nucleozin, has recently been identified that targets the viral nucleoprotein (NP). These inhibitors are thought to act as "molecular staples" that stabilize interactions between NP monomers, promoting the formation of nonfunctional aggregates. Here we detail the inhibitory mechanism of nucleozin, finding that the drug has both early-and late-acting effects on the IAV life cycle. When present at the start of infection, it inhibited viral RNA and protein synthesis. However, when added at later time points, it still potently blocked the production of infectious progeny but without affecting viral macromolecular synthesis. Instead, nucleozin blocked the cytoplasmic trafficking of ribonucleoproteins (RNPs) that had undergone nuclear export, promoting the formation of large perinuclear aggregates of RNPs along with cellular Rab11. This effect led to the production of much reduced amounts of often markedly smaller virus particles. We conclude that the primary target of nucleozin is the viral RNP, not NP, and this work also provides proof of the principle that IAV replication can be effectively inhibited by blocking cytoplasmic trafficking of the viral genome.

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Influenza Nucleoprotein: Promising Target for Antiviral Chemotherapy

Cited by 45 publications

References 147 publications

Mechanism of Action for Respiratory Syncytial Virus Inhibitor RSV604

Mechanism of Action for Respiratory Syncytial Virus Inhibitor RSV604

NXT1, a Novel Influenza A NP Binding Protein, Promotes the Nuclear Export of NP via a CRM1-Dependent Pathway

Nucleozin Targets Cytoplasmic Trafficking of Viral Ribonucleoprotein-Rab11 Complexes in Influenza A Virus Infection

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